The metabolic routes in which various compounds are biosynthesized from arachidbnic acid, are collectively called the xe2x80x9cArachidonic Acid Cascade.xe2x80x9d
Leukotriene B4 (LTB4) is one of many products resulting from the arachidonic acid cascade.
Moreover, LTB4 in high concentration has been detected at the sites of various inflammatory conditions, for example, rheumatism, spinal arthritis (see Klickstein L. B., Shapleigh, C. and Goetzl, E. J. (1980) J. Clin. Invest., 66, 1166-1170), gout (Rae, S. A., Davidson, E. M. and Smith, M. J. H. (1982) Lancet II 1122-1123), psoriasis (see Grabbe, J., Czarnetzki, B. M., Rosenbach, T. and Mardin, M. (1984) J. Invest. Dermatol., 82, 477-479), ulcerative colitis (see Sharon, P. and Stenson, W. F. (1984) Gastroenterology 86, 453-460). and respiratory disease (see O""Driscoll, B. R., Cromwell, O. and Kay, A. B. (1984) Clin. Exp., Immunol., 55, 397-404). The facts described above show that LTB4 is deeply related to various forms of inflammation. It has been suggested that compounds antagonizing LTB4 activity may be valuable in the treatment of inflammatory diseases caused by tissue degrading enzymes and reactive chemicals liberated by tissue-infiltrating and aggregating polymorphonuclear leukocytes.
For example, PCT Japanese National Publication No. 6-502164 describes novel monocylic or bicyclic aryl compounds are selectively antagonistic to LTB4 and are useful for treatment of rheumatoid arthritis, gout, psoriasis and inflammatory bowel disease. Japanese Unexamined Patent Publication (Kokai) No. 4-244023 describes that omega 6 series unsaturated fatty acids such as xcex3-linolenic acid are useful for treatment of arrhythmia, acute myocardial infarction etc, by inhibiting production of LTB4. Japanese Unexamined Patent Publication No. 5-310668 describes that a novel leucine derivative has an inhibitory action to LTA4 hydrolase and is useful for treatment and prophylaxis of allergic diseases such as bronchial asthma, various inflammatory diseases, and ischemia-reperfusion disorders. Japanese Unexamined Patent Publication (Kokai) No. 1-190656 discloses that novel leukotriene B3 dimethyl amide has an antagonistic action to LTB4 and is useful as anti-inflammatory drug, anti-rheumatic drug and gout-treatment drug.
The article, xe2x80x9cSecond Generation Leukotriene B4 Receptor Antagonists Related to SC-41930: Heterocyclic Replacement of the Methyl Ketone Pharmacophorexe2x80x9d, J. Med Chem, 1995, 38, p.858-868 by Penning, Thomas D. et. al.; describes heterocycle substituted LTB4 antagonists.
Pyrazole LTB4 antagonists are disclosed in the article, xe2x80x9cLeukotriene B4 (LUB4) Receptor Antagonists: A Series of (Hydroxyphenyl)pyrazolesxe2x80x9d by Richard W. Harper, et. al., J. Med Chem, 1994, 37, pgs. 2411-2420.
Leukotriene B4 antagonists, inclusive of diphenyl ethers such as 2-[2-propyl-3-[3-[2-ethyl-5-hydroxy-4-(4-fluorophenyl)phenoxylpropoxy]phenoxy]benzoic acid, are described in U.S. Pat. No. 5,462,954, the disclosure of which is incorporated herein by reference. The same type of leukotriene B4 antagonists are described in the article, xe2x80x9cSynthetic and Structure/Activity Studies on Acid-Substituted 2-Arylphenols: Discovery of 2-[2-Propyl-3-(3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxy]benzoic Acid, a High-Affinity Leukotriene B4 Receptor Antagonistxe2x80x9d by J. Scott Sawyer, et. al., Journal of Medicinal Chemistry, 1995, 38, pgs. 4411-4432.
These diphenyl ether leukotriene B4 antagonists, in combination with a 2xe2x80x2,2xe2x80x2-difluoronucleoside analog (e.g., GEMCITABINE HCl, have also been found to have utility in the treatment of various cancers, as further described in Provisional Patent Application Serial No. 60/164786, filed 11 Nov. 1999, the disclosure of which is incorporated herein by reference.
Currently, anti-inflammatory drugs are classified as steroidal and non-steroidal. Although these drugs provide anti-inflammatory action they all have drawbacks which limit their use. A more recent approach to the moderation of inflammation focuses on blocking the action of arachidonic acid metabolites.
Leukotriene B4 antagonists are useful for a wide variety of Inflammatory Diseases, but it is expected that various of these antagonists will show superior results with particular disease states. This is one reason it is desirable to develop new leukotriene B4 antagonists such as the compounds of this invention.
The present invention is directed to novel heterocycle substituted diphenyl compounds of formula (I) 
Another aspect of this invention are pharmaceutical compositions containing the compounds of formula (I).
Another aspect of this invention is a method of using the compounds of the invention in the prevention and treatment of LTB4 induced illnesses.
Another aspect of this invention is a compound of formula (I) for use as a medicament in the treatment or prevention of Inflammatory Diseases.
Another aspect of this invention is a process for preparing a compound of Formula (I).